Factor IX dalcinonacog alfa
The leading recombinant human Factor IX on the market for treating acute bleeding episodes in individuals with hemophilia B is delivered intravenously (due to its short half-life) and is therefore not ideal for prophylactic treatment. Extended half-life agents used for prophylaxis require intravenous dosing and have a prolonged period of low activity levels with increased risk of spontaneous bleeding. Catalyst created an improved and potent Factor IX, dalcinonacog alfa, formerly known as CB 2679d/ISU304, for the potential subcutaneous prophylactic treatment of hemophilia B. Dalcinonacog alfa has shown significantly higher potency in preclinical and early clinical studies compared with other Factor IX products on the market and in development. In June 2017, the Company’s partner, ISU Abxis, initiated a Phase 1/2 proof-of-concept study in individuals with hemophilia B.
Factor IX dalcinonacog alfa Phase 1/2 proof-of-concept study in individuals with severe hemophilia B - ongoing
The subcutaneous proof-of-concept study (NCT03186677) of dalcinonacog alfa in individuals with severe hemophilia B is an open-label trial with an intravenous cross-over to subcutaneous dosing. The trial is being conducted in collaboration with ISU Abxis (KOSDAQ: 086890). The objective of the trial is to study the pharmacokinetics, subcutaneous bioavailability and activity levels achieved with escalating subcutaneous doses of dalcinonacog alfa, as well as observe steady-state levels that result from daily dosing for six and nine days. The trial is being conducted at three centers in South Korea. The trial is expected to enroll up to 17 individuals and be completed in 2018.
Data from Cohorts 1, 2 and 3 of the trial were presented at the 59th American Society of Hematology (ASH) Annual Meeting and Exposition in December 2017. Results showed that intravenous dalcinonacog alfa is approximately 22 times more potent than BeneFIX and that subcutaneous delivery of dalcinonacog alfa significantly increases Factor IX activity half-life.
In December 2017, the Korean Ministry of Food and Drug Safety (MFDS) approved a protocol amendment to accelerate the trial by omitting single dose Cohort 4 and moving directly to a multi-dose Cohort 5.
In February 2018, Catalyst announced positive top-line data from Cohort 5 of the proof-of-concept study at the 11TH Annual Congress of The European Association for Haemophilia and Allied Disorders (EAHAD). After six days of once-daily SQ dosing, dalcinonacog alfa increased Factor IX activity levels in five patients, who were each dosed daily with 140 IU/kg subcutaneously, from very low levels after washout of prior therapy to a median Factor IX activity level of 16% (range 11.5-18%). This is well into the mild hemophilia range (5-40%) and is higher than a level required to prevent hemarthrosis.
In April 2018, the proof-of-concept trial was amended to add a sixth cohort in which each patient received a single intravenous loading dose of dalcinonacog alfa followed by nine daily subcutaneous doses. To date, two patients (out of a planned three to five) have been enrolled and efficacy was observed in both patients. During the treatment period, Factor IX activity levels remained above 20% after the intravenous loading dose in both patients. The first patient then had a progressive increase in trough Factor IX activity level to 34% and the second patient to a trough activity level of 31%. Subsequent blood samples showed the presence of a transient neutralizing antibody in one patient and a neutralizing antibody in the second. Prior to Cohort 6, no neutralizing antibodies had been detected in any of the patients treated with dalcinonacog alfa. Catalyst is conducting an analysis to assess the cause and impact of the antibody observations prior to dosing any further subjects in Cohort 6.
Learn more about our strategic collaboration with ISU Abxis.
Factor IX dalcinonacog alfa Phase 1/2 proof-of-concept study in individuals with severe hemophilia B design
Dalcinonacog alfa has been granted orphan medicinal product designation in Europe to treat individuals with hemophilia B. Orphan medical products in Europe are required to be judged superior to currently available therapies to receive the designation and must be confirmed to be superior when marketing authorization is granted. Dalcinonacog alfa was also awarded orphan drug designation by the U.S. Food and Drug Administration (FDA) in 2017.